RESUMO
Parkinson disease (PD) is a progressive neurodegenerative disorder that is often accompanied by motor and psychiatric symptoms. Various approaches have been proposed for the treatment of PD. Here, we investigated the effect of a low dose of fatty acid amide hydrolase inhibitor URB597 (as an enhancer of endocannabinoid anandamide levels), exercise or their combination on some behavior alterations in PD mice lesioned by 6-hydroxydopamine (6-OHDA). The impact of swimming exercise (5×/week for 4 weeks) and URB597 (0.1 mg/kg, 2×/week for 4 weeks) on the anxiety-related behavior (elevated plus maze; EPM), depression-related behavior (tail suspension test; TST), and passive avoidance memory (step-down task) was examined in the sham and male NMRI mouse of PD model. The results show that URB597 prevented memory deficits and elicited antidepressant- and anxiolytic-like effects but did not affect hypolocomotion in the PD mice. However, URB597 did not have a significant effect on the performance of the sham mice in the performed tests. Moreover, swimming training abolished depressive- and anxiogenic-like behaviors and increased locomotion without affecting memory deficits in the PD mice. Meanwhile, swimming decreased immobility time and increased locomotion in the sham mice. Furthermore, URB597 in association with swimming training prevented all deficits induced in the PD mice, while this combination impaired memory and produced the positive effects on depression- and anxiety-related behaviors and locomotion of the sham mice. It is concluded that although URB597 or exercise alone had positive effects on most behavioral tests, their combination improved all parameters in the PD mice.
Assuntos
Doença de Parkinson , Animais , Comportamento Animal , Benzamidas , Carbamatos , Modelos Animais de Doenças , Teste de Labirinto em Cruz Elevado , Elevação dos Membros Posteriores , Masculino , Camundongos , Camundongos Endogâmicos , Oxidopamina/toxicidadeRESUMO
Morphine and tramadol are the opioid analgesic drugs acting via activation of µopioid receptors. It is important to understand which mechanism (synergistic or additive antinociceptive activity) induced potent antinociceptive effect by coadministration of morphine and tramadol. Identification of new strategies that can potentiate analgesic effects of opioids will be good therapeutic approaches for pain relief. To this aim, male mice were cannulated in the left ventricle by a stereotaxic instrument. A tailflick test was used to record the pain threshold. The results revealed that intracerebroventricularly injection of morphine induced an antinociceptive effect in nonsensitized and morphinesensitized mice. We found that infusion of tramadol produced an antinociceptive response in nonsensitized mice, whereas tramadol in doses of 0.5 and 1 µg/mouse induced analgesia in morphinesensitized mice. Coinjection of a noneffective dose of tramadol or morphine (0.25 µg/mouse) with different doses of morphine or tramadol (0.25, 0.5, and 1 µg/mouse) respectively potentiated the analgesic effect of the previous drug. An isobolographic analysis of data was performed, indicating a synergistic interaction between morphine and tramadol in nonsensitized and morphinesensitized mice. Our data indicated that both morphine and tramadol elicit more antinociceptive response in morphine sensitized mice; there is a synergistic effect between morphine and tramadol upon induction of analgesic effect in nonsensitized and morphinesensitized mice.
Assuntos
Tramadol , Analgésicos Opioides/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Morfina/farmacologia , Dor , Medição da DorRESUMO
AIMS: Previous investigations demonstrated that tramadol, as a painkiller, similar to morphine induces tolerance and dependence. Furthermore, the cannabinoid receptor 1 (CB1R) located in the nucleus accumbens (NAc) plays a critical role in morphine-induced conditioning. Therefore, the main objective of this study was to evaluate the role of NAc CB1R in tramadol induced conditioning and reinstatement. MAIN METHODS: In the present experiment, the effect of NAc CB1 receptors on tramadol induced conditioning was tested by microinjecting of arachidonylcyclopropylamide (ACPA, CB1R agonist) and AM 251 (CB1R inverse agonist) in the NAc during tramadol-induced conditioning in the adult male Wistar rats. In addition, the role of NAc CB1R in the reinstatement was also evaluated by injecting ACPA and AM 251 after a 10-days extinction period. KEY FINDINGS: The obtained data revealed that the administration of tramadol (1,2, and 4 mg/kg, ip) dose-dependently produced conditioned place preference (CPP). Moreover, intra-NAc administration of ACPA (0.25, 0.5, and 1 µg/rat) dose-dependently induced conditioning, while the administration of AM-251 (30, 60, and 120 ng/rat) induced a significant aversion. In addition, the administration of a non-effective dose of AM251 during tramadol conditioning inhibited conditioning induced by tramadol. On the other hand, the administration of ACPA after extinction induced a significant reinstatement. Notably, the locomotor activity did not change among groups. SIGNIFICANCE: Previous studies have shown that tramadol-induced CPP occurs through µ-opioid receptors. The data obtained in the current study indicated that CB1R located in the NAc is involved in mediating conditioning induced by tramadol. Besides, CB1R also plays a vital role in the reinstatement of tramadol-conditioned animals. It might be due to the effect of opioids on enhancing the level of CB1R.
Assuntos
Analgésicos Opioides/efeitos adversos , Condicionamento Psicológico/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Receptor CB1 de Canabinoide/fisiologia , Tramadol/efeitos adversos , Analgésicos Opioides/administração & dosagem , Animais , Condicionamento Clássico , Relação Dose-Resposta a Droga , Extinção Psicológica/efeitos dos fármacos , Masculino , Núcleo Accumbens/metabolismo , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Tramadol/administração & dosagemRESUMO
Clinical studies have demonstrated that the NMDA receptor antagonist ketamine produces rapid antidepressant responses. There are safety concerns and adverse effects that limit the utilization of ketamine in psychiatry. Some studies have suggested combination therapy for optimal ketamine use. In this study, we evaluated the potential for combination therapy of ineffective doses of ketamine and fatty acid amide hydrolase inhibitor URB597 for the treatment of depression and pain in male NMRI mice. Intraperitoneal administration of ketamine (10 mg/kg) at the time intervals of 115, 145, and 160 min and ketamine (5 mg/kg) at the time interval of 160 min after administration increased the tail-flick latency, indicating an antinociceptive effect. The same doses of ketamine decreased immobility time in the forced swim test (FST), showing an antidepressant-like effect. Moreover, URB597 at the doses of 0.5 and 1 mg/kg induced an antinociceptive effect, while it at the dose of 1 mg/kg produced an antidepressant-like response. Furthermore, co-administration of the ineffective doses of ketamine (2.5 mg/kg) and URB597 (0.1 mg/kg) caused antinociceptive and antidepressant-like effects, while each one of them alone did not alter the performance of mice in the FST and tail-flick tests. It should be noted that none of the treatments alter animal locomotor activity compared to the control group. Therefore, the combined administration of ineffective doses of ketamine and URB597 might be an effective strategy in the therapy of depression and pain.
Assuntos
Analgésicos/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Benzamidas/farmacologia , Carbamatos/farmacologia , Ketamina/farmacologia , Amidoidrolases/antagonistas & inibidores , Analgésicos/administração & dosagem , Animais , Antidepressivos/administração & dosagem , Benzamidas/administração & dosagem , Carbamatos/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Ketamina/administração & dosagem , Masculino , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Dor Nociceptiva/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , NataçãoRESUMO
Chronic stress induces hippocampal-dependent memory deficits, which can be counterbalanced with prolonged exercise. On the other hand, the ß-carboline alkaloid harmane exerts potential in therapies for Alzheimer's and depression diseases and modulating neuronal responses to stress. The present study investigated the effect of chronic treatment of harmane alone or during treadmill running on spatial memory deficit in restraint-stressed mice. To examine spatial memory, adult male NMRI mice were subjected to the Y-maze. Intraperitoneal administration of harmane (0.6â¯mg/kg, once/ 48â¯h for 25â¯days) decreased the percentage of time in the novel arm and the number of novel arm visits, indicating a spatial memory deficit. A 9-day restraint stress (3â¯h/day) also produced spatial learning impairment. However, a 4-week regime of treadmill running (10â¯m/min for 30â¯min/day, 5â¯days/week) aggravated the stress impairing effect on spatial learning of 3-day stressed mice compared to exercise/non-stressed mice. Moreover, harmane (0.3â¯mg/kg) associated with exercise increased the number of novel arm visits in 9-day stressed mice compared to harmane/exercise/non-stressed or 9-day stressed group. It should be noted that none of these factors alone or in combination with each other had no effect on locomotor activity. Taken together, these data suggest that there is no interaction between harmane and exercise on spatial memory in stress condition.